Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/65—Tetracyclines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/243—Platinum; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• Product comprising mikanolide. dihydromikanolide or an analog thereof in combination with another anticancer agent for therapeutic use in the treatment of cancer
• the present invention relates to a product comprising at least mikanolide, dihydromikanolide or an analog thereof in combination with at least one other anticancer agent for simultaneous, separate or spread over time therapeutic use in the treatment of cancer .
• Mikanolide and dihydromikanolide can be obtained from extracts of Mikania plants, for example from the plant Mikania micrantha.
• Mikanolide and dihydromikanolide are sesquiterpenes of the germacranes family, that is to say having the 4-isopropyl-1,7-dimethylcyclodecane for hydrocarbon backbone (Herz et al., Tetrahedron Lett. (1967) 3111-3115 ; Kiang et al., Phytochemistry (1968) 7: 1035-1037; Cuenca et al., J. Nat. Prod. (1988), 51, 625-626).
• Rj represents a hydrogen atom or a radical SR 4 or NR R S ;
• R 2 represents SR 6 or NR 6 R 7 ;
• R 3 represents OH, O (CO) R 14 , OSiR, 5 R ⁇ 6 R ⁇ 7 , O (CO) OR 18 or O (CO) NHR 18 ;
• R 4 and R 6 represent, independently, an alkyl radical, a cycloalkyl, cycloalkylalkyl, hydroxyalkyl radical or alternatively one of the aryl or aralkyl radicals optionally substituted on their aryl group by one or more radicals chosen from alkyl, hydroxy or alkoxy radicals
• R 5 and R 7 represent, independently, a hydrogen atom, an alkyl radical, a cycloalkyl, cycloalkylalkyl, hydroxyalkyl radical or also one of the aryl or aralkyl radicals optionally substituted on their aryl group by one or more radicals chosen from alkyl, hydroxy or alkoxy radicals
• R 4 and R 5 can form together with the nitrogen atom which carries them a heterocycle of 5 to 7 members, the complementary members being chosen from the radicals -CRgRç, -, -NR, 0 -, -O- and -S-, it being understood however that there
• R g , R 10 , R n and R 13 represent, independently each time they intervene, a hydrogen atom or an alkyl, alkoxycarbonyl or aralkyl radical
• Rg and R 12 representing, independently each time they intervene , a hydrogen atom or each of R ⁇ , and R 12 may form, with R s and R ,, respectively, a radical -O- (CH 2 ) 2 -O- attached on either side to the atom of carbon which carries it, such a radical being present however only once at most per radical NR 4 R 5 or NR 6 R 7 , represent, independently each time they occur, a hydrogen atom or a radical alkyl;
• R M represents an alkyl, cycloalkyl or adamantyl radical or one of the aryl, heteroaryl, aralkyl or heteroaralkyl radicals optionally substituted on their aryl or heteroaryl group by one or more radicals chosen from a halogen atom and the alkyl, haloalkyl, nitro radicals, hydroxy, alkoxy, alkylthio or phenyl, or also R ] 4 is such that R 14 -COOH represents a natural amino acid or the optical enantiomer of such an amino acid;
• R 15 , R 16 and R 17 independently represent an alkyl radical or a phenyl radical
• R 18 represents an alkyl, cycloalkyl or adamantyl radical or one of the aryl, heteroaryl, aralkyl or heteroaralkyl radicals optionally substituted on their aryl or heteroaryl group by one or more radicals chosen from a halogen atom and the alkyl, haloalkyl, nitro radicals, hydroxy, alkoxy, alkylthio or phenyl;
• the subject of the invention is therefore a product comprising at least mikanolide, dihydromikanolide or an analog thereof, optionally in the form of a pharmaceutically acceptable salt, in combination with at least one other anticancer agent for simultaneous therapeutic use , separated or spread over time, in the treatment of cancer.
• analog of mikanolide or of dihydromikanolide will correspond to the general formula (I) as described above.
• a compound of general formula (I) having at least one of the following characteristics will be preferred:
• R j represents a hydrogen atom or an NR 4 R 5 radical
• R 2 represents a radical NR 6 R 7 ;
• R 3 represents OH or a radical O (CO) R I4 , OSiR 15 R, 6 R ⁇ 7 or O (CO) NHR I8 .
• a compound of general formula (I) will be such that it has at least one of the following characteristics:
• Rj represents a hydrogen atom
• R 2 represents a radical NR 6 R 7 ;
• R 3 represents a radical O (CO) R 14 , OSiR 15 R ⁇ 6 R 17 or O (CO) NHR lg .
• a compound of general formula (I) will be such that it has at least one of the following characteristics:
• R j represents a hydrogen atom
• R 2 represents a radical NR 6 R 7 and preferably a radical NR 6 R 7 in which R 6 and R 7 are independently chosen from a hydrogen atom and an alkyl radical
• R 3 represents a radical O (CO) R ! 4 , OSiR 15 R ] 6 R 17 or O (CO) NHR 18-
• R 2 will most preferably represent an NR 6 R 7 radical in which R 6 and R 7 are alkyl radicals, and in particular an NR 6 R 7 radical in which R 6 and R 7 are methyl radicals.
• R 3 will most preferably represent an O (CO) NHR 18 radical.
• R 4 will represent an alkyl or aralkyl radical
• R 5 will represent a hydrogen atom or an alkyl radical
• R 4 and R 5 will form together with the atom d nitrogen which carries them a heterocycle of 5 to 7 members, the complementary members being chosen from the radicals -CRgRg-, -NR 10 -, -O- and -S-.
• R 8 will represent, independently each time it intervenes, a hydrogen atom or an alkyl radical (and preferably a hydrogen atom) and R c, will represent each time that it intervenes an atom of hydrogen.
• R 10 will represent, independently each time it occurs, a hydrogen atom or an alkyl radical.
• R s will represent an alkyl or aralkyl radical
• R 7 will represent a hydrogen atom or an alkyl radical, or alternatively R 6 and R 7 will form together with the atom d nitrogen which carries them a heterocycle of 5 to 7 links, the complementary links being chosen from the radicals -CR ⁇ R 12 -, -NR 13 -, -O- and -S-
• R n will independently represent each time it occurs, a hydrogen atom or an alkyl or alkoxycarbonyl radical (and preferably a hydrogen atom) or alternatively R n and R J2 will once represent together a radical -O- (CH 2 ) 2 - O- attached on both sides to the carbon atom which carries it.
• R I3 will represent, independently each time it occurs, a hydrogen atom or an alkyl radical.
• R M will preferably represent an alkyl or cycloalkyl radical, or one of the aryl or heteroaryl radicals optionally substituted by a halogen atom or a haloalkyl or phenyl radical. More preferably, R 14 will represent a cycloalkyl radical or one of the aryl or heteroaryl radicals optionally substituted by a halogen atom or a haloalkyl radical. Even more preferably, R M will represent a cyclohexyl radical or one of the phenyl, thienyl or benzothienyl radicals optionally substituted by a halogen atom.
• the compounds of general formula (I) will preferably be such that R, 5 , R ⁇ 6 and R 17 represent alkyl radicals.
• the compounds of general formula (I) will be such that one of the radicals R 15 , R 16 and R 17 represents a tert-butyl radical and the other two represent methyl radicals.
• R 18 represents an alkyl, cycloalkyl or adamantyl radical, or one of the aryl or heteroaryl radicals optionally substituted by a halogen atom or an alkyl, haloalkyl, alkoxy radical, alkylthio or phenyl.
• R 1g will represent a cycloalkyl radical or one of the aryl or heteroaryl radicals optionally substituted by an alkyl, alkoxy or alkylthio radical.
• R 1S will represent one of the phenyl, thienyl or benzothienyl radicals optionally substituted by an alkyl, alkoxy or alkylthio radical.
• the radical NR 4 R 5 preferably represents one of the pyrrolyl, piperidyl, piperazinyl, morpholinyl radicals or thiomorpholinyl optionally substituted by an alkyl radical (the latter preferably being a methyl or ethyl radical, and more preferably a methyl radical) on one of its carbon or nitrogen atoms, or by a radical -O- ( CH 2 ) 2 -O- attached on both sides to a carbon atom.
• an alkyl radical the latter preferably being a methyl or ethyl radical, and more preferably a methyl radical
• the radical NR 4 R 5 will represent one of the pyrrolyl, piperidyl, piperazinyl, morpholinyl or thiomorpholinyl radicals optionally substituted by an alkyl radical (the latter preferably being a methyl radical) on one of its carbon or nitrogen atoms.
• the radical NR 6 R 7 preferably represents one of the pyrrolyl, piperidyl, piperazinyl, morpholinyl radicals or thiomorpholinyl optionally substituted by an alkyl radical (the latter preferably being a methyl or ethyl radical, and more preferably a methyl radical) on one of its carbon or nitrogen atoms, or by a radical -O- ( CH 2 ) 2 -O- attached on both sides to a carbon atom.
• an alkyl radical the latter preferably being a methyl or ethyl radical, and more preferably a methyl radical
• the radical NR 6 R 7 will represent one of the pyrrolyl, piperidyl, piperazinyl, morpholinyl or thiomorpholinyl radicals optionally substituted by an alkyl radical (the latter preferably being a methyl radical) on one of its carbon or nitrogen atoms.
• an alkyl radical the latter preferably being a methyl radical
• the analog of mikanolide or of dihydromikanolide will correspond to the general formula (I)
• Rj represents a hydrogen atom or a radical SR 4 or NR 4 R 5 ;
• R 2 represents SR 6 or NR 6 R 7 ;
• R 3 represents OH, O (CO) R 14 , O (CO) OR 14 , or OSiR 15 R 16 R 17 ;
• R 4 , R s , R 6 and R 7 independently represent a hydrogen atom, an alkyl radical, a cycloalkyl, cycloalkylalkyl, hydroxyalkyl radical or even one of the aryl or aralkyl radicals optionally substituted on their aryl group by a or radicals chosen from alkyl, hydroxy or alkoxy radicals,
• R 4 and R 5 can form together with the nitrogen atom which carries them a heterocycle of 5 to 7 members, the complementary members being chosen from the radicals -CR 8 Rg-, -NR 10 -, -O- and -S-, it being understood however that there can be only one link chosen from -O- or -S- in said heterocycle, and R 6 and R 7 can form together with the nitrogen atom which carries them a heterocycle of 5 to 7 members, the complementary members being chosen from the radicals -CR n R 12 -, -NR 13 -, -O- and -S-, it being understood however that 'there can be only one link chosen from -O- or -S- in said heterocycle,
• R 8 , R 10 , R ⁇ and R 13 represent, independently each time they intervene, a hydrogen atom or an alkyl, alkoxycarbonyl or aralkyl radical
• g and R 12 representing, independently each time they intervene , a hydrogen atom or each of Rg and R 12 can form, with R 8 and R n respectively, a radical -O- (CH 2 ) 2 -O- attached on both sides to the carbon atom which carries, such a radical being present however only once at most per radical NR 4 R 5 or NR 6 R 7 , represent, independently each time they occur, a hydrogen atom or an alkyl radical;
• R, 4 , R 15 , R 16 and R I7 independently represent a hydrogen atom, an alkyl radical or one of the aryl or aralkyl radicals optionally substituted on their aryl group by one or more radicals chosen from alkyl radicals , hydroxy or alkoxy;
• R represents a hydrogen atom or an SR 4 or NR 4 R 5 radical
• R 2 represents SR 6 or NR 6 R 7 ;
• R 3 represents OH, O (CO) R 14 , O (CO) OR 14 , or OSiR ⁇ 5 R 16 R 17 ;
• R 4 , R 5 , R 6 and R 7 independently represent a hydrogen atom, an alkyl radical, a cycloalkyl, cycloalkylalkyl, hydroxyalkyl radical or even one of the aryl or aralkyl radicals optionally substituted on their aryl group by a or radicals chosen from alkyl, hydroxy or alkoxy radicals, R 4 and R 5 can form together with the nitrogen atom which carries them a heterocycle of 5 to 7 members, the complementary links being chosen from radicals -CR 8 Rg-, -NR I0 -, -O- and -S-, it being understood however that there can be only one link chosen from -O- or -S- in said heterocycle, and Rg and R 7 being able to form together with the nitrogen atom which carries them a heterocycle of 5 to 7 members, the complementary members being chosen from the radicals -CR n R 12 -, -NR I3 -, -O- and -S-
• R 8 , R 10 , R n and R 13 represent, independently each time they intervene, a hydrogen atom or an alkyl, alkoxycarbonyl or aralkyl radical
• Rg and R 12 representing, independently each time they intervene , a hydrogen atom or each of R g and R 12 can form, with R 8 and R n respectively, a radical -O- (CH 2 ) 2 -O- attached on either side to the carbon atom which carries it, such a radical being present however only once at most per radical NR 4 R 5 or NR 6 R 7 , represent, independently each time they occur, a hydrogen atom or an alkyl radical;
• R 14 , R 15 , R 16 and R 17 independently represent a hydrogen atom, an alkyl radical or one of the aryl or aralkyl radicals optionally substituted on their aryl group by one or more radicals chosen from alkyl radicals, hydroxy or alkoxy;
• alkyl or lower alkyl when it is not given more precision, is meant in the present application a linear or branched alkyl radical containing from 1 to 12 carbon atoms, and preferably from 1 to 6 carbon atoms.
• cycloalkyl when it is not given more precision, is meant in the present application a monocyclic carbon system containing from 3 to 7 carbon atoms.
• haloalkyl is meant in the present application an alkyl radical in which at least one of the hydrogen atoms (and optionally all) is replaced by a halogen atom.
• carbocyclic or heterocyclic aryl when it is not given more precision, is meant in the present application a carbocyclic or heterocyclic system comprising from one to three condensed rings of which at least one is an aromatic ring, a system being said to be heterocyclic when at least one of the cycles which compose it comprises one or more heteroatoms (O, N or S).
• aryl when it is not given more precision, is meant in the present application a carbocyclic aryl radical.
• heteroaryl is meant in the present application a heterocyclic aryl radical.
• heterocycle when no further details are given, in the present application is meant a non-aromatic heterocycle comprising from 3 to 7 links (and preferably from 5 to 7 links) whose heteroatoms are chosen from atoms d 'nitrogen, oxygen and sulfur.
• haloalkyl is meant in the present application an alkyl radical in which at least one of the hydrogen atoms (and optionally all) is replaced by a halogen atom.
• halogen atom in the present application is meant fluorine, chlorine, bromine or iodine atoms.
• alkoxy, haloalkoxy, hydroxyalkyl, cycloalkylalkyl, aralkyl and heteroaralkyl radicals is meant in the present application, respectively, the alkoxy, haloalkoxy, hydroxyalkyl, cycloalkylalkyl and aralkyl radicals, the alkyl, haloalkyl, cycloalkyl, aryl and heteroaralkyl radicals of which have the meanings indicated above.
• valine valine
• Leu leucine
• Ile isoleucine
• Met methionine
• Met methionine
• phenylalanine Phe
• asparagine Asn
• glutamic acid Glu
• glutamine Gin
• His histidine
• lysine Lys
• arginine Arg
• aspartic acid Asp
• Gly glycine
• alanine Ala
• serine serine
• Thr threonine
• Trp tryptophan
• cysteine cysteine
• Cys proline
• Pro proline
• linear or branched alkyl having from 1 to 6 carbon atoms is meant in particular in the present application the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl radicals, hexyl, isohexyl.
• alkoxy is meant in particular in the present application the methoxy, ethoxy and isopropoxy radicals, and in particular the methoxy and ethoxy radicals.
• cycloalkyl is meant in particular in the present application the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals.
• haloalkyl is meant in particular in the present application the trifluoromethyl radical.
• haloalkoxy is meant in particular in the present application the trifluoromethoxy radical.
• carbocyclic aryl is meant in particular in the present application the phenyl, naphthyl and phenanthryl radicals, preferably the phenyl and naphthyl radicals and more preferably the phenyl radical.
• heterocyclic aryl is understood to mean in the present application in particular the pyrrolyl, furannyl, benzofurannyl, thienyl, benzothienyl, pyridyl, pyrimidinyl, triazinyl, imidazolyl, oxazolyl, thiazolyl, indolyl and quinolyl, and preferably the furannyl, benziuryl radicals.
• benzothienyl By aralkyl is meant in particular in the present application a phenalkyl radical, and preferably the benzyl radical.
• heteroaralkyl is meant in particular in the present application a thienylalkyl, furannylalkyl, pyrrolylalkyl and thiazolylalkyl radical (the alkyl radical of said radicals is preferably a methyl radical), and preferably a thienylalkyl radical (preferably thienylmethyl).
• heterocycle is meant in particular in the present application the piperidinyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl, telxahydropyrannyl and thiazolidinyl radicals.
• pharmaceutically acceptable salt means in particular in the present application addition salts of inorganic acids such as hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate , succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate. Also falling within the scope of the present invention, when they can be used, the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference may be made to "Knows selection for basic drugs", Int. J. Phann.
• enzyme inhibitors among which:
• camptothecin and camptothecin analogs in the form of analogs comprising a six-membered lactone E ring such as, for example, the compounds described in PCT patent application WO 94/11376, in the form of analogs comprising a seven-membered E-lactone ring such as for example the compounds described in PCT patent applications WO 97/00876 and WO 99/11646 or also in the form of open tetracyclic analogs such as for example the compounds described in the PCT patent application WO 99/33829);
• CDKs - cyclin-dependent kinase inhibitors
• GSK-3 inhibitors such as those described in the PCT patent application not yet published PCT / FR01 / 04048; - MAP kinase inhibitors; MAP kinase kinase inhibitors such as 2- (2-amino-3-methoxyphenyl) -4H-chromen-4-one (compound PD 98059 from the company Parke Davis, described in PCT patent application WO 96/22985); - protein kinase C inhibitors; tyrosine kinase inhibitors; telomerase inhibitors;
• alkylating agents such as cis-platinum, busulfant, chlorambucil, Fisofosfamide or procarbazine;
• intercalating agents such as doxorubicin, daunorubicin, bleomycin, epirubicin, elliptinium, or mitoxantrone; anti-metabolic agents such as 5-fluorouracyl, gemcitabine or purine derivatives such as mercaptopurine; differentiators; spindle cell poisons such as taxol and its analogs; angiogenesis inhibitors; anti-hormones or steroid receptor antagonists; antioxidants; antisense agents; anti-p53 agents (gene therapy); chemoprevention agents;
• camptothecin analogue comprising a seven-membered lactonic ring E
• it will preferably be chosen from the following compounds:
• mikanolide In general, it will be preferred to combine with mikanolide, dihydromikanolide or one of its analogs an anti-cancer agent having a different mechanism of action than said mikanolide, dihydromikanolide or the like.
• the anti-cancer agent used in combination with mikanolide, dihydromikanolide or an analog thereof will be chosen from enzyme inhibitors, alkylating agents, intercalating agents, anti-metabolic agents, spindle poisons cell, antibiotics and antibodies.
• the anti-cancer agent used in combination with mikanolide, dihydromikanolide or an analog thereof will be chosen from enzyme inhibitors and alkylating agents.
• heterotimeric protein G transduction inhibitors prenyltransferase inhibitors, Cdc25 phosphatase inhibitors (especially Cdc25C phosphatases), CDK inhibitors, GSK-3 inhibitors and MAP kinase kinase inhibitors will be preferred.
• the enzymatic inhibitors will be chosen from heterotimeric protein G transduction inhibitors, prenyltransferase inhibitors, Cdc25 phosphatase inhibitors (especially Cdc25C phosphatases), CDK inhibitors and GSK-3 inhibitors.
• the enzyme inhibitors will be heterotimeric protein G transduction inhibitors and prenyltransferase inhibitors (in particular farnesyltransferase inhibitors).
• heterotrimeric protein G transduction inhibitors those which are active after one hour are preferred, for example those described in PCT patent application WO 00/02881 (as opposed to those which are active after 24 hours as those described in PCT patent application WO 00/02558).
• the farnesyltransferase inhibitors will be preferred, and in particular those described in PCT patent application WO 00/39130 such as 4- (2-bromophenyl) - 1 - ⁇ 2- [1 - ((4-cyano -3-methoxy) phenylmethyl) imidazo-5-yl] - 1 -oxoethyl ⁇ - 1, 2-dihydrofluoroimidazol [1, 2a] [1, 4] -benzodiazepine.
• the anti-cancer agent used in combination with mikanolide, dihydromikanolide or an analog thereof will be chosen from inhibitors of heterotrimeric G protein transduction and alkylating agents.
• the anti-cancer agent used in combination with mikanolide, dihydromikanolide or an analog thereof will be a heterotrimeric protein G transduction inhibitor, this will be a compound of formula general (II)
• X represents R 12 and Y represents R ⁇ , or X and Y complete a 6-membered ring, the set XY representing the radical -CH (Rs) -CH (R 9 ) -;
• R1 represents H, an alkyl or lower alkylthio radical
• R 2 and R 3 independently represent H or a lower alkyl radical
• R 4 represents H 2 or O
• R 5 represents H, or one of the lower alkyl, lower cycloalkylalkyl, lower alkenyl, lower alkynyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals possibly being substituted by radicals chosen from the group consisting of a lower alkyl radical, -OR 10 , -S (O) m R ⁇ o (m representing 0, 1, or 2), -N (R ⁇ o) (Rn), -NC (O) -R ⁇ o, -NH- (SO 2 ) -R ⁇ o, -CO2-R10, C (O) -N (R ⁇ o) (RnX and - (SO 2 ) -N (R ⁇ o) (Rn);
• R 6 and R 7 independently represent H, a radical -C (O) -NH-CHR 3 -C ⁇ 2 Ri 4 , or one of the lower alkyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals possibly optionally be substituted by radicals chosen from the group consisting of OH, alkyl or lower alkoxy, N (R ⁇ o) (R ⁇ ), COOH, CON (R ⁇ o) (Rn), and halo, or Rg and R 7 together form a radical aryl or a heterocycle;
• R ⁇ and R 9 independently represent, H, or one of the lower alkyl, aryl, lower arylalkyl, heterocycle or heterocycle lower alkyl radicals, these radicals possibly being substituted by radicals chosen from the group consisting of OH, alkyl or lower alkoxy, N (R ⁇ o) (R ⁇ ), COOH, CON (R ⁇ 0 ) (Rn) and halo, or Rs and R 9 together form an aryl radical or a heterocycle;
• Rio and Ru independently represent H, an aryl or heterocycle radical, or an alkyl, arylalkyl or heterocycle lower alkyl radical;
• R 12 represents NR 9 , S, or O;
• R 13 represents a lower alkyl radical optionally substituted by a radical chosen from the lower alkyl radicals, -OR 10 , -S (O) m R ⁇ o (m representing 0, 1, or 2) and -N (R ⁇ o) (R ⁇ );
• R 4 represents H or a lower alkyl radical
• the compound of general formula (II) will correspond to the general sub-formula (II) ! .
• R will represent H
• R 2 and R 3 will independently represent H or a methyl radical
• R 4 will represent O
• R 5 will represent a lower cycloalkylalkyl, lower aryloxyalkyl, lower aralkoxyalkyl, aryisuifonylalkyl radical
• R 6 will represent an aryl radical optionally substituted by an alkyl or lower alkoxy radical (preferably methyl or methoxy) and each of R 7 , R 8 and Rg will represent H.
• the following compounds will be preferred in particular:
• the compound of general formula (II), associated with mikanolide, dihydromikanolide or an analog thereof will be 7- (2-amino-1-oxo-3-thiopropyl) -8- (cyclohexylmethyl) -2-phenyl-
• the anti-cancer agent used in combination with mikanolide, dihydromikanolide or an analog thereof will be a Cdc25 phosphatase inhibitor, this will be a compound of general formula ( III)
• R 1 represents a hydrogen atom or an alkyl or cycloalkyl radical, - (CH 2 ) -XY or - (CH 2 ) -Z- R 5 R 6 , R 1 which can also, when W represents O, also represent a carbocyclic aryl radical optionally substituted from 1 to 3 times by substituents independently chosen from a halogen atom and an alkyl, haloalkyl or alkoxy radical, X representing a bond or a linear or branched alkylene radical having 1 to 5 carbon atoms, Y representing a saturated carbon ring system having 1 to 3 condensed rings independently chosen from 3 to 7-membered rings, or Y representing a saturated heterocycle having 1 to 2 heteroatoms chosen independently from O, N and S and attached to the radical X by an N or CH link, said saturated heterocycle also counting from 2 to 6 additional links chosen independently from -CHR 7 -, -CO-, -NR 8 -, -O- and -S-
• R 5 and R 6 being independently selected from a hydrogen atom, an alkyl, aralkyl or - (CH 2 ) n -OH radical in which n represents an integer from 1 to 6, or R 5 and R 6 forming together with l nitrogen atom a 4- to 7-membered heterocycle comprising from 1 to 2 heteroatoms, the links necessary to complete the heterocycle being chosen independently from the radicals -CR I2 R 13 -, -O-, -S- and -NR 14 - , R 12 and R 13 independently representing each time they intervene a hydrogen atom or an alkyl radical, and R 14 representing a hydrogen atom or an alkyl or aralkyl radical, or alternatively R 14 representing a phenyl radical optionally substituted 1 to 3 times with substituents independently chosen from a halogen atom and an alkyl or alkoxy radical,
• R 2 representing a hydrogen atom or an alkyl radical; or also R 1 and R 2 forming together with the nitrogen atom a 4- to 7-membered heterocycle comprising from 1 to 2 heteroatoms, the links necessary to complete the heterocycle being chosen independently from the radicals -CR 15 R 16 - , -O-, -S- and -NR 17 -, R 15 and R 16 independently representing each time they intervene a hydrogen atom or an alkyl radical, and R 17 representing a hydrogen atom or a radical alkyl or aralkyl;
• R 3 represents a hydrogen atom, a halogen atom, or an alkyl, haloalkyl or alkoxy radical
• R 4 represents an alkyl, cycloalkyl, cycloalkylalkyl, cyano, amino radical, -CH 2 -COOR 18 , -CH 2 -CO-NR 19 R 20 or -CH 2 -NR 21 R 22 , or alternatively R 4 represents an aryl radical heterocyclic optionally substituted 1 to 3 times with substituents chosen independently from a halogen atom and an alkyl, haloalkyl or alkoxy radical, R 18 representing a hydrogen atom or an alkyl radical, R 19 representing a hydrogen atom, a radical alkyl or an aralkyl radical in which the aryl group is optionally substituted from 1 to 3 times by substituents independently chosen from the group consisting of a halogen atom, an alkyl radical, a haloalkyl radical, an alkoxy radical, a haloalkoxy radical, a hydroxy radical , a nitro radical, a cyano radical, the phenyl
• W represents O or S
• the compounds of general formula (III) used in combination with mikanolide, dihydromikanolide or an analog thereof will include at least one of the following characteristics:
• R 1 representing an alkyl, cycloalkyl, - (CH 2 ) -XY or - (CH 2 ) -Z-NR 5 R 6 radical;
• R 2 representing a hydrogen atom or the methyl or ethyl radical
• R 3 representing a hydrogen atom, a halogen atom or an alkoxy radical
• R 4 representing an alkyl radical, -CH 2 -COOR 18 or -CH 2 -CO-NR 19 R 20 or -CH 2 -NR 21 R 22 .
• the compounds of general formula (III) will preferably be such that the radical X will preferably represent a bond or a linear alkylene radical containing from 1 to 5 carbon atoms.
• the compounds of general formula (III) will be such that the radical Y will represent a saturated carbon ring system having 1 to 3 condensed rings independently chosen from rings of 3 to 7 members, or Y will represent a carbocyclic aryl radical ( preferably optionally substituted by 1 to 3 radicals chosen from a halogen atom and an alkyl, haloalkyl, alkoxy, haloalkoxy, SO 2 NHR 9 or NR 10 R ⁇ radical, and more preferably optionally substituted by 1 to 3 radicals chosen from a halogen atom and an alkyl radical, alkoxy, SO 2 NHR 9 or NR 10 R ⁇ ) or Y will represent a heterocyclic aryl radical, said heterocyclic aryl radical preferably being chosen from 5-membered aryl radicals (
• the compounds of general formula (III) will preferably be such that the radical Z will represent an alkylene radical having 1 to 5 carbon atoms.
• the compounds of general formula (III) will be such that R 5 and R 6 will be independently chosen from a hydrogen atom and an alkyl radical, or alternatively R 5 and R 6 will form together with the nitrogen atom which carries them a 4- to 7-membered heterocycle comprising from 1 to 2 heteroatoms, said heterocycle then preferably being one of the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl and thiomorpholinyl radicals optionally substituted by 1 to 3 alkyl radicals ( and preferably by 1 to 3 methyl radicals).
• the compounds of general formula (III) will preferably also be such that R 18 represents a hydrogen atom or the methyl or ethyl radical.
• the compounds of general formula (III) will be such that the radicals R 7 , R 12 , R 13 , R 15 , R 16 , R 26 , R 27 , R 32 , R 33 and R 34 will preferably be chosen independently from a hydrogen atom and a methyl radical and the radicals R 8 , R 14 , R 17 , R 28 and R 34 will preferably be chosen independently from a hydrogen atom and a methyl or benzyl radical.
• R 19 represents a hydrogen atom, an alkyl radical or a benzyl radical and R 20 represents a hydrogen atom or the methyl radical, as well as those in which R 19 and R 20 form, together with the nitrogen atom which carries them, a 4- to 7-membered heterocycle comprising from 1 to 2 heteroatoms, said heterocycle then being of preferably one of the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl and thiomorpholinyl radicals optionally substituted with 1 to 3 alkyl radicals (and preferably optionally substituted with 1 to 3 methyl radicals).
• R 21 and R 22 in the compounds of general formula (III) preference will be given to the cases in which R 21 represents a hydrogen atom, an alkyl radical or a benzyl radical and R 22 represents a d atom. hydrogen or the methyl radical, as well as those in which R 21 and R 22 form, together with the nitrogen atom which carries them, a 4- to 7-membered heterocycle comprising from 1 to 2 heteroatoms, said heterocycle then preferably being one of the azetidinyl, pyrrolidinyl radicals , piperidinyl, piperazinyl, homopiperazinyl, morpholinyl and thiomo holinyl optionally substituted with 1 to 3 alkyl radicals (and preferably optionally substituted with 1 to 3 methyl radicals).
• the compounds of general formula (III) used in combination with mikanolide, dihydromikanolide or an analog thereof, the invention will include at least one of the following characteristics:
• R 1 representing an alkyl, cycloalkyl, (cycloalkylalkyl or - (CH 2 ) -Z-NR 5 R 6 radical;
• R 2 representing a hydrogen atom or the methyl radical
• R 3 representing a hydrogen atom, a halogen atom or the methoxy radical
• R 4 representing an alkyl radical or -CH 2 -NR 21 R 22 .
• the compounds of general formula (III) used in combination with mikanolide, dihydromikanolide or an analog thereof will include at least one of the following characteristics:
• R 1 representing a radical - (CH 2 ) -Z-NR 5 R 6 ;
• R 3 representing a hydrogen atom or a halogen atom (said halogen atom preferably being a chlorine atom);
• R 4 representing an alkyl radical, and preferably an alkyl radical containing from 1 to 4 carbon atoms, and more preferably still a methyl or ethyl radical.
• the compounds of general formula (III) used in combination with mikanolide, dihydromikanolide or an analog thereof will be such that W represents O.
• R 1 represents an aryl radical, and in particular a phenyl radical, optionally substituted from 1 to 3 times with substituents independently chosen from a halogen atom and an alkyl, haloalkyl or alkoxy radical.
• R 1 represents a phenyl radical optionally substituted by a halogen atom (said halogen atom preferably being a fluorine atom).
• Compounds of general formula (III) preferred for use in combinations according to the present invention are the compounds described in Examples 53 to 69 below, as well as their pharmaceutically acceptable salts.
• a compound of general formula (III) en chooses to be combined with mikanolide, dihydromikanolide or an analog thereof it will be preferred to use 5 - ⁇ [2- (dimethylamino) ethyl] amino ⁇ - 2-methyl-1,3-benzothiazole-4,7-dione or one of its pharmaceutically acceptable.
• the anti-cancer agent used in combination with mikanolide, dihydromikanolide or an analog thereof will be an inhibitor of CDK and / or GSK-3, the latter will be a compound of general formula (IV)
• A represents a hydrogen atom, a halogen atom, a formyl, cyano, nitro, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol) -3-ylidenemethyl, alkylcarbonyl, aralkylcarbonyl or heteroaralkylcarbonyl radical, or even a radical -L -NR'R 2 in which L represents an alkylene radical and R 1 and R 2 are independently selected from a hydrogen atom and an alkyl radical or R 1 and R 2 taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 links, the complementary links being chosen independently from the group composed of -CH 2 -, -NR 3 -, -S- and -O-, R 3 representing each time an atom hydrogen or an alkyl radical; X represents a hydrogen atom, an alkylthio, aralkylthio, alkylthioxo or aralky
• Y represents NH or an oxygen atom
• Z represents a bond or an alkyl or alkylthioalkyl radical
• Ar represents a carbocyclic aryl radical optionally substituted from 1 to 3 times by radicals independently chosen from a halogen atom, the cyano radical, the nitro radical, an alkyl or alkoxy radical and a NR 7 R 8 radical in which R 7 and R 8 independently represent a hydrogen atom or an alkyl radical or R 7 and R 8 taken together with the nitrogen atom which carries them form a 5 to 7 membered heterocycle, the complementary members being independently chosen from the group consisting of - CH 2 -, -NR 9 -, -S- and -O-, R 9 independently representing each time that it intervenes a hydrogen atom or an alkyl radical, or alternatively Ar represents a heterocyclic aryl radical having 5 or 6 links and the heteroatom (s) of which are chosen from nitrogen, oxygen or sulfur atoms, said heteroatoms possibly being oxidized (Ar may represent, for example, the oxidopyridyl radical) and said ary radical the heterocyclic which may be optional
• the compounds of general formula (IV) will be such that they have at least one of the following characteristics: • A represents a hydrogen atom, a halogen atom, a formyl, cyano, nitro, guanidinoaminomethylenyl, (1, 3-dihydro-2-oxoindol) -3-ylidenemethyl, alkylcarbonyl or aralkylcarbonyl radical, or also a radical -L- NR'R 2 in which L represents an alkylene radical and R 1 and R 2 are independently chosen from a hydrogen atom and an alkyl radical or R 1 and R 2 taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 links, the complementary links being chosen independently from the group composed of -CH 2 -, -NR 3 -, -S- and -O-, R 3 representing each time an atom d hydrogen or an alkyl radical;
• X represents a hydrogen atom, an alkylthio or alkylthioxo radical, or also a NR 4 R 5 radical in which R 4 represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical optionally substituted by one or more amino radicals, a radical aralkyl in which the aryl radical is optionally substituted by one or more radicals chosen from a halogen atom and the alkyl or alkoxy radicals, or alternatively R 4 represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or alkyl radicals and R 5 represents a hydrogen atom, or then R 4 and R 5 taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group composed of -CH 2 -, -NR 6 -, -S- and -O-, R 6 independently representing each
• the compounds of general formula (IV) will be such that they have at least one of the following characteristics:
• A represents a halogen atom, a formyl radical, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol) -3-ylidènemethyl or alkylcarbonyl, or alternatively a radical -L- ⁇ R 2 in which L represents a methylene radical and R 1 and R 2 are chosen independently from a hydrogen atom and an alkyl radical or R 1 and R 2 taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group consisting of -CH 2 -, -NR 3 - and -O-, R 3 representing independently each time it intervenes a hydrogen atom or an alkyl radical;
• X represents an alkylthio or alkylthioxo radical, or also a NR 4 R 5 radical in which R 4 represents an alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical optionally substituted by one or more amino radicals, or also R 4 represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or more alkyl radicals and R 5 represents a hydrogen atom, or else R 4 and R 5 taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 links, the complementary links being chosen independently from the group composed of -CH 2 -, -NR 6 - and -O-, R 6 representing each time an atom hydrogen or an alkyl or hydroxyalkyl radical;
• Ar represents a carbocyclic aryl radical optionally substituted from 1 to 3 times by radicals independently chosen from a halogen atom and a radical
• NR 7 R 8 in which R 7 and R 8 independently represent a hydrogen atom or an alkyl radical or R 7 and R 8 taken together with the nitrogen atom which carries them form a 5- to 7-membered heterocycle, the complementary links being independently selected from the group consisting of -CH 2 -, -NR 9 - and -O-, R 9 representing independently each time it intervenes a hydrogen atom or an alkyl radical,
• Ar represents a heterocyclic aryl radical having 5 or 6 members and the heteroatom (s) of which are chosen from nitrogen and oxygen atoms, said heteroatoms possibly being oxidized and said heterocyclic aryl radical possibly being substituted by one or radicals independently chosen from alkyl, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl radicals.
• the compounds of general formula (IV) will be such that they exhibit at least one of the following characteristics:
• A represents a halogen atom, a formyl radical, guanidinoaminomethylenyl, (1,3-dihydro-2-oxoindol) -3-ylidenemethyl or alkylcarbonyl, or alternatively a radical -L-NR'R 2 in which L represents a methylene radical and R 1 and R 2 are independently chosen from a hydrogen atom and an alkyl radical or R 1 and R 2 taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group consisting of -CH 2 -, -NR 3 - and -O-, R 3 representing independently each time it intervenes a hydrogen atom or an alkyl radical;
• X represents an alkylthio (and preferably methylthio) or alkylthioxo (and preferably methylthioxo) radical, or alternatively a NR 4 R 5 radical in which R 4 represents a alkyl radical, a hydroxyalkyl radical, a cycloalkyl radical (and preferably cyclohexyl) optionally substituted by one or more amino radicals, or alternatively R 4 represents a heteroaryl or heteroarylalkyl radical, the heteroaryl radical of the heteroaryl or heteroarylalkyl radicals being optionally substituted by one or alkyl radicals and R 5 represents a hydrogen atom, or then R 4 and R 5 taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being chosen independently from the group compound of -CH 2 - and -NR 6 -, R 6 independently representing each time it intervenes a hydrogen atom or an alkyl or hydroxyalkyl radical;
• Ar represents a carbocyclic aryl radical (said carbocyclic aryl radical preferably being a phenyl radical) optionally substituted from 1 to 3 times by radicals chosen independently from a halogen atom and a NR 7 R 8 radical in which R 7 and R 8 represent independently a hydrogen atom or an alkyl radical or R 7 and R 8 taken together with the nitrogen atom which carries them form a heterocycle of 5 to 7 members, the complementary members being independently selected from the group consisting of -CH 2 - and -NR 9 -, R 9 representing independently each time it involves an alkyl radical,
• Ar represents a heterocyclic aryl radical having 5 or 6 members and the heteroatom (s) of which are chosen from nitrogen and oxygen atoms (said heterocyclic aryl radical preferably being a pyridyl radical), said heteroatoms possibly being oxidized and said heterocyclic aryl radical possibly being optionally substituted by one or more radicals independently chosen from the alkyl, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl radicals.
• a compound of general formula (IV) which is particularly preferred for obtaining a product according to the invention will be 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) - 4- (3-fluorophenylmethylamino) -pyrazolo [1, 5- a] -l, 3,5-triazine, 8-bromo-
• the anti-cancer agent used in combination with mikanolide, dihydromikanolide or an analog thereof will be a farnesyltransferase inhibitor, this will be a compound of general formula (V )
• ni 0 or 1
• X represents, independently each time it occurs, (CHR ii ) n3 (CH 2 ) n4 Z (CH 2 ) n5 ;
• Z represents O, N (R 12 ), S, or a bond
• n3 representing, independently each time it intervenes, 0 or 1;
• n4 and n5 representing, independently each time they occur, 0, 1, 2, or 3;
• Y represents, independently each time it intervenes, CO, CH 2 , CS, or a bond
• R 1 represents one of the radicals each of R 2 , R 11 , and R 12 representing, independently each time it occurs, H or an optionally substituted radical chosen from the group consisting of a (Ci- 6 ) alkyl radical and an aryl radical, said optionally substituted radical being optionally substituted by at least one radical chosen from the radicals R 8 and R 30 , each substituent being chosen independently of the others;
• R 3 represents, independently each time it occurs, H or an optionally substituted radical chosen from the group consisting of (C ⁇ -6 ) alkyl, (C 2 - 6 ) alkenyl, (C 2 - 6 ) alkynyl, ( C 3. 6 ) cycloalkyl,
• each of R 4 and R 5 represents, independently each time it occurs, H or an optionally substituted radical chosen from the group consisting of (C ⁇ . 6 ) alkyl, (C 3 _ 6 ) cycloalkyl, aryl and heterocyclyl radicals, said optionally substituted radical being optionally substituted by at least one radical chosen from the radicals R 30 , each substituent being chosen independently of the others, or R 4 and R 5 taken together with the carbon atoms to which they are attached together form an aryl radical;
• R 6 represents, independently each time it occurs, H or an optionally substituted radical chosen from the group consisting of (C ⁇ -6 ) alkyl, (C 2-6 ) akenyl, (C 3 _ 6 ) cycloalkyl, ( C 3-6 ) cycloalkyl (C 1. 6 ) alkyl, (C 5 _ 7 ) cycloalkenyl, (C 5. 7 ) cycloalkenyl (C ⁇ .
• each of R 8 and R 9 representing, independently each time it intervenes, H, (C ⁇ -6 ) alkyl, (C 2-6 ) alkenyl, (C 2 - 6 ) alkynyl, aryl, or aryl (C ⁇ -6 ) alkyl;
• R 6 and R 7 can be taken together with the carbon atoms to which they are attached to form an aryl or cyclohexyl radical;
• R 21 represents, independently each time it occurs, H or an optionally substituted radical chosen from the group consisting of (C ⁇ _ 6 ) alkyl and aryl (Ci- 6 ) alkyl radicals, said optionally substituted radical being optionally substituted with at least a radical chosen from the radicals R 8 and R 30 , each substituent being chosen independently of the others;
• R 22 represents H, (C ⁇ . 6 ) alkylthio, (C 3 - 6 ) cycloalkylthio, R 8 -CO-, or a substituent of formula
• each of R 24 and R 25 represents, independently each time it occurs, H, (C ⁇ _ 6 ) alkyl or aryl (C ⁇ -6 ) alkyl;
• R 30 represents, independently each time it intervenes, ( ⁇ alkyl, -OR 8 , -S (O) n6 R 8 , -S (O) n7 N (R 8 R 9 ), -N (R 8 R 9 ), -CN, -NO 2 , -CO 2 R 8 , -CON (R 8 R 9 ), -NCO-R 8 , or halogen, each of n6 and n7 representing, independently each time it occurs, 0, 1 or 2;
• said heterocyclyl group is azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl , isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoa
• aryl radical being phenyl or naphthyl
• each of X 1 , X 2 , and X 3 representing, independently, H, a halogen atom, -NO 2 , -NCO-R 8 , -CO 2 R 8 , -CN, or -CON (R 8 R 9 ) ;
• n2 representing an integer from 1 to 6, and each of X 4 and X 5 representing, independently, H, (C ⁇ - 6 ) alkyl or aryl, or X 4 and X 5 forming, taken together, a radical (C 3 _ 6 ) cycloalkyl;
• the compounds of general formula (V) will be those in which are found, independently, the radicals having the following characteristics:
• R 21 representing an aralkyl radical in which the aryl group may optionally be substituted by one or more radicals chosen from a halogen atom and the cyano, hydroxy, alkoxy, amino, alkylamino and dialkylamino radicals;
• R 4 representing an aryl radical optionally substituted by one or more radicals chosen from a halogen atom and the hydroxy, alkoxy, amino, alkylamino and dialkylamino radicals;
• X representing an alkylene radical having 1 to 6 carbon atoms
• each of X 1 , X 2 , and X 3 independently representing H or a halogen atom.
• the anti-cancer agent used in combination with mikanolide, dihydromikanolide or an analog thereof is preferably chosen from 7- (2-amino-1-oxo-3- thiopropyl) -8- (cyclohexylmethyl) -2-phenyl- 5,6,7,8-tetrahydroimidazo [1,2a] pyrazine, cisplatin, 8-bromo-2- (1R-isopropyl- 2-hy (koxyethylamino) - 4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine, the
• the anticancer agent used in combination with mikanolide, dihydromikanolide or an analog thereof will be chosen from 7- (2-amino-1-oxo-3-thiopropyl) -8- (cyclohexylmethyl) - 2-phenyl-5,6,7,8-tetrahydroimidazo [1,2a] pyrazine and cis-platinum.
• the cancer treated with the product according to the invention will be chosen from cancers of the esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, breast, cervix uteri, corpus endometrium, ovaries, prostate, testes, bladder, kidneys, liver, pancreas, bones, connective tissue, skin, e.g. melanomas, eyes, brain and central nervous system, as well as thyroid cancer, leukemia, Hodgkin's disease, non-Hodgkin's lymphomas and multiple myelomas.
• the cancers treated with the product according to the invention will be cancers of the digestive system, and in particular cancers of the oral cavity, the esophagus, the stomach, the intestines, the colon or the rectum.
• the subject of the invention is also a pharmaceutical composition comprising at least one of the products according to the invention, in other words a composition containing, as active principle, the combination of mikanolide, dihydromikanolide or an analog thereof with another anti cancer agent.
• compositions comprising a product according to the invention can be in the form of solids, for example powders, granules, tablets, capsules, liposomes or suppositories.
• Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.
• compositions comprising a product according to the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups.
• suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
• a medicament according to the invention may be done by topical, oral, parenteral route, by injection (intramuscular, subcutaneous, intravenous, intraperitoneal, etc.), etc.
• the route of administration will of course depend on the type of disease to be treated.
• the dose of a product according to the present invention varies according to the mode of administration, the age and the body weight of the subject to be treated as well as the state of the latter, and it will be decided ultimately by the attending physician or veterinarian. Such an amount determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount”.
• - cis-platinum from 50 to 80 mg / m 2 ; - taxol: from 1 to 20 mg / kg (intraperitoneal route) or 1 to 3 mg / kg (intravenous route).
• composition of the product of the invention can be prepared by the methods described below.
• R 3 is not OH
• the intermediate obtained is treated with one of the reagents of general formula R 14 (CO) -Hal (or an equivalent reagent such as for example the anhydride (R 14 (CO )) 2 O), R, 8 O (CO) -Hal, Hal-Si R 15 R 16 R 17 (Hal representing a halogen atom) or R 18 -NCO to obtain the desired final compound.
• this reaction is carried out in an aprotic solvent such as dichloromethane, trichloroethane, acetonitrile, tetrahydrofuran or toluene, at a temperature preferably between 0 ° C and 110 ° C and optionally in presence of a base such as triethylamine or 4-dimethylamino ⁇ yridine.
• aprotic solvent such as dichloromethane, trichloroethane, acetonitrile, tetrahydrofuran or toluene
• a base such as for example dimethylaminopyridine
• a coupling agent such as, for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HC1).
• a nucleophile such as a primary or secondary amine HNR 4 R 5
• a thiol R 4 SH in the presence of a base
• an inert solvent such as tetrahydrofuran or acetone
• a second reaction is carried out using a compound of general formula R 14 (CO) -Hal (or an equivalent reagent such as for example the anhydride (R 14 ( CO)) 2 O), R 18 O (CO) -Hal, Hal-SiR 15 R 16 R 17 (Hal representing a halogen atom) or R 18 -NCO to obtain the desired final compound.
• This reaction can be carried out in a similar way to that described in CAS 1.
• An additional method for obtaining compounds with R 3 ⁇ OCOR ] 4 consists in treating the intermediate alcohol with the acid R 14 -COOH in the presence of a base, such as for example dimethylaminopyridine, and an agent coupling, such as for example 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HC1).
• a base such as for example dimethylaminopyridine
• an agent coupling such as for example 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HC1).
• the compounds of sub-formula (I) 2 can be prepared, scheme A.4, from mikanolide by addition of a nucleophile such as a primary or secondary amine HNR 6 R 7 , or also of a thiol R 6 SH in the presence of a base, in an inert solvent such as tetrahydrofuran or acetone, at a temperature preferably between 0 ° C and 50 ° C, and more preferably at room temperature.
• a nucleophile such as a primary or secondary amine HNR 6 R 7
• a thiol R 6 SH in the presence of a base
• an inert solvent such as tetrahydrofuran or acetone
• Certain compounds of the invention can be prepared in the form of pharmaceutically acceptable salts according to the usual methods. With regard to these salts, a person skilled in the art may usefully consult the article by Gould et al., "Knows selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
• the compounds of general formula (III), in which R 1 , R 2 , R 3 , R 4 and W are as described above, are obtained by treatment of the compounds of general formula (A), in which L represents a methoxy radical, a halogen atom or a hydrogen atom and R 3 , R 4 and W have the same meaning as in general formula (III), with amines of general formula NR ⁇ H in a protic solvent such as methanol or ethanol, at a temperature between 0 ° C and 50 ° C and optionally in the presence of a base such as, for example, diisopropylethylamine (Yasuyuki Kita et al., J. Org. Chem. (1996), 61, 223-227).
• a protic solvent such as methanol or ethanol
• the compounds of general formula (III) can be obtained in the form of a mixture of the 2 position isomers, but it is then possible to separate them by chromatography on a silica column in an appropriate eluent.
• the compounds of general formula (III) in which R 3 represents a halogen atom (Hal) can be obtained, scheme 16M, from the compounds of general formula (III) in which R 3 represents a hydrogen atom, for example by the action of N-chlorosuccinimide or N-bromosuccinimide in an aprotic solvent such as dichloromethane or tetrahydrofuran (Paquette and Farley, J. Org. Chem. (1967), 32, 2725-2731), by the action of a aqueous solution of sodium hypochlorite (bleach) in a solvent such as acetic acid (Jagadeesh et al., Synth Commun.
• aprotic solvent such as dichloromethane or tetrahydrofuran
• the compounds of general formula (A) are obtained by treatment with cerium (IV) and ammonium nitrate (Beneteau et al., Eur. J. Med. Chem. (1999), 34 (12), 1053-1060).
• the compounds of general formula (A) are obtained by oxidation of the compounds of general formula (B), for example by using FeCl 3 in an acid medium (Antonini et al., Heterocycles (1982), 19 (12 ), 2313-2317) or Fremy's salt (potassium nitrosodisulfonate). (Ryu et al., Bioorg. Med.
• a reagent comprising a hypervalent iodine such as [bis (acetoxy) iodo] benzene or [bis (trifluoroacetoxy) iodo] benzene in aqueous acetonitrile at a temperature preferably between -20 ° C and room temperature (or about 25 ° C), and preferably at about -5 ° C (Kinugawa et al ., Synthesis, (1996), 5, 633-636).
• a hypervalent iodine such as [bis (acetoxy) iodo] benzene or [bis (trifluoroacetoxy) iodo] benzene in aqueous acetonitrile at a temperature preferably between -20 ° C and room temperature (or about 25 ° C), and preferably at about -5 ° C (Kinugawa et al ., Synthesis, (1996), 5, 633-636).
• the compounds of general formula (A) can be obtained, scheme C.3, by halooxidation of the compounds of general formula (B) in which L and R 3 represent atoms of hydrogen and Q and / or Q ′ is (are) chosen from an amino radical and a hydroxy radical by the action, for example, of potassium or sodium perchlorate in an acid medium (Ryu et al., Bioorg. Med. Chem. Lett. (1999), 9, 1075-1080).
• the compounds of general formula (B) can in particular be obtained from the nitro derivatives of formula (B.ii) in which Q or Q 'represents a nitro radical by reduction methods well known to those skilled in the art such as, for example hydrogenation in the presence of a palladium catalyst or treatment with tin chloride in hydrochloric acid .
• R represents a radical -CH 2 -NR 21 R 22
• the compounds of general formula (B) can be obtained, scheme C.5, from the compounds of general formula (B.iii) in which R 4 represents the methyl radical, which is first subjected to a radical reaction using N-bromosuccinimide in the presence of an initiator such as 2,2'-azobis ( 2-methylpropionitrile) or dibenzoylperoxide in an aprotic solvent such as carbon tetrachloride (CC1 4 ) at a temperature preferably between room temperature (ie about 25 ° C) and 80 ° C and under irradiation with a UV lamp ( Mylari et al., J. Med. Chem. (1991), 34, 108-122), followed by substitution of the intermediate of general formula (B.iv) with amines of formula H ⁇ R 21 R 22 with R 21 and R 22 are as defined above.
• an initiator such as 2,2'-azobis ( 2-methylpropionitrile) or di
• the compounds of general formula (B) can be obtained from the compounds of general formula (B) in which R 4 represents the radical -CH 2 -COOH, by the conventional methods of peptide synthesis (M. Bodansky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)), for example in tetrahydrofuran, dichloromethane or dimethylformamide in the presence of a coupling reagent such as cyclohexylcarbodiimide (DCC), l, l'-carbonyldiimidazole (CDI) (J. Med. Chem.
• DCC cyclohexylcarbodiimide
• CDI l'-carbonyldiimidazole
• the compounds of general formula (B) in which R 4 represents -CH 2 -COOH can be obtained from the compounds of general formula (B) in which R 4 represents the radical -CH 2 -COOR 18 in which R 18 represents a alkyl radical by hydrolysis of the ester function under conditions known to a person skilled in the art.
• the compounds of general formula (B) can be obtained, scheme C.6, from the compounds of general formula (C) in which L, R 3 , Q, Q 'and W are as defined below. above by condensation with the orthoester of general formula RC (OR) 3 in which R is an alkyl radical, for example in the presence of a catalytic amount of an acid such as, for example, paratoluenesulfonic acid, at a temperature between room temperature and 200 ° C and preferably around 110 ° C (Jenkins et al., J. Org. Chem.
• orthoesters are known industrial products available from usual suppliers. The preparation of orthoesters by treating various nitrile compounds with hydrochloric gas in an alcohol is known to those skilled in the art.
• the compounds of general formula (B) in which L, R 3 , R 4 , Q, Q 'and W are as defined above can also be obtained from the compounds of general formula (C) in which L, R 3 , Q, Q 'and W are as defined above by condensation of the latter with an acid chloride of formula R 4 -COCl under an inert atmosphere and in a polar and slightly basic solvent such as N-methyl- 2-pyrrolidinone (Brembilla et al., Synth. Commun (1990), 20, 3379-3384).
• the compounds of general formula (B) in which L, R 3 , R 4 , Q, Q 'and W are as defined above can also be obtained from the compounds of general formula (C) in which L, R 3 , Q, Q 'and W are as defined above by condensation with an aldehyde of general formula R 4 -CHO then treatment of the Schiff base obtained with an oxidizing agent such as [bis (acetoxy) iodo] benzene , ferric chloride or dimethyl sulfoxide (Racane et al., Mon ⁇ tsh. Chem.
• an oxidizing agent such as [bis (acetoxy) iodo] benzene , ferric chloride or dimethyl sulfoxide
• the compounds of general formula (B) in which L, R 3 , R 4 , Q, Q 'and W are as defined above can also be obtained from the compounds of general formula (C) in which L, R 3 , Q, Q 'and W are as defined above by condensation with a nitrile of general formula R 4 -CN in a mixture of solvents of the methanol / glacial acetic acid type at a temperature between room temperature (ie approximately 25 ° C) and 100 ° C (Nawwar and Shafik, Collect. Czech Chem. Commun. (1995), 60 (12), 2200-2208).
• a number of triazolopyrazines of general formula (IV) can be easily prepared according to the procedures described in US Patent 4,565,815.
• the other compounds of general formula (IV) according to the invention can be prepared in a few steps, scheme Dl, from the compounds of general formula (IV ⁇ in which A 'represents a hydrogen atom or a halogen atom and X' represents a hydrogen atom or an alkylthio radical.
• a ' represents a hydrogen atom or a halogen atom
• X' represents a hydrogen atom or an alkylthio radical.
• the preparation of the compounds of general formula (III) is described in US Patent 4,565,815 or in Kobe et al., J Het. Chem. (1974), 11 (2), 199 and s.
• the starting compound of general formula (IV) j is such that X 'represents alkylthio and preferably methylthio.
• the compound of general formula (IVX is first subjected to a substitution reaction with the alcohol or the amine of general formula (IV) 2 to give the compound of general formula (IV) 3.
• the compound of general formula (IV) 3 is then treated with we't ⁇ -chloroperbenzoic acid and then with the amine of general formula R 4 NHR S to finally give the compound of general formula (IV).
• These reactions are preferably carried out in a solvent such as chloroform.
• the compound of general form (IV) 4 represented in diagram D.4 is used as starting compound, for example.
• This compound is a compound of general formula (IV) in which A represents H and its synthesis has therefore been described previously.
• the compound of general formula (IV) 4 is for example first treated with an excess of (chloromethylene) -dimethylammonium chloride in a polar aprotic solvent such as an acetonitrile-dimethylformamide mixture. This makes it possible to obtain compounds of general formula (IV) in which A represents the formyl radical.
• These compounds can be prepared in a conventional manner from the compound of general formula (IV) 4 , for example according to the process represented in scheme D.5.
• the compound of general formula (TV) 4 can for example be treated at low temperature (for example at -78 ° C) successively with butyllithium in a polar aprotic solvent such as ethyl ether or tetrahydrofuran then the compound of general formula ( IV) S in which Hal represents a halogen atom, before being hydrolyzed by water slightly acidified to give the compound of general formula (IV) in which A represents a radical -L-NR'R 2 .
• the compound of general formula (IV) in which A represents a formyl radical is converted into the compound of general formula (IV) in which A represents a cyano radical, scheme D.8, by reaction with hydroxylamine in a mixture of formate sodium and formic acid. The reaction is preferably carried out with heating.
• the compounds of Examples 1 to 52 are compounds of general formula (I).
• the nomenclature used for the examples is in principle in accordance with the IUPAC standards. It was determined using ACD / Name ® software (version 4.53) for Examples 1 to 36 and using ACD / Name ® software (version 5.0) for Examples 37 to
• Example 1 12-diisopropylaminomethyl-7-methyl-3, 6,10,15-tetraoxapentacyclo [12.2.1.0 2 ' 4 .0 5 ' 7 .0 913 ] heptadec-l (17) -ene-ll, 16- dione:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 2.
• the expected product is obtained in the form of a white powder.
• Example 7 ll-hydroxy-3,8-dimethyl-4,14-dioxo- 5,9,15-trioxatetracyclo fumarate [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16) -ene- 12- yl (dimethyl) ammonium:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 5.
• the expected product is obtained in the form of a white powder. Melting point: 210 ° C
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 5.
• the expected product is obtained in the form of a white powder.
• Example 11 1- [1 l-hydroxy-3,8-dimethyl-4,14-dioxo- 5,9,15-trioxatetracyclo [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16) -ene- 12-yl] - ethyl 4-piperidinecarboxyate:
• Example 12 12- (4-benzylpiperidino) -1 l-hydroxy-3,8-dimethyl- 5,9,15-trioxatetracyclo [11.2.1.0 z ' 6 .0 810 ] hexadec-13 (16) -ene-4 , 14-dione:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 5.
• the expected product is obtained in the form of a white powder.
• Example 14 12- (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) -ll-hydroxy-3,8-dimethyl- 5,9,15-trioxatetracyclo [11.2.1.0 2.6 . 0 810 ] hexadec-13 (16) -ene-4,14-dione:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 5.
• the expected product is obtained in the form of a white powder.
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 5.
• the expected product is obtained in the form of a white powder.
• Example 16 1 l- (tert-butyldimethylsiloxy) -12-dimethylamino-3,8-dimethyl- 5,9, lS-trioxatetracycIo [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16) -ene-4 , 14-dione:
• Example 17 3,8-dimethyl-12- (4-methylpiperidino) -4,14-dioxo- 5,9,15-trioxatetracyclo acetate [11.2.1.0 2 ' 6 .0 8 10 ] hexadec-13 (16) -en-ll-yle:
• Example 20 11-hydroxy-12-isobutylsulfanyl-3-isobutylsulfanylmethyl-8-methyl-5,9,15-trioxatetracyclo [11.2.1.0 2 ' â .0 8, 0 ] hexadec-13 (16) -ene-4, 14-dione:
• Example 22 12- (dimethylamino) -3,8-dimethyl-4,14-dioxo- 5,9,15-trioxatetracyclo benzoate [11.2.1.0 2 ' â .0 810 ] hexadec-13 (16) -en- ll-yle:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• Example 23 12- (dimethylamino) -3,8-dimethyl-4,14-dioxo- 5,9,15-trioxatetracyclo acetate [11.2.1.0 2 ' 6 .0 8 10 ] hexadec-13 (16) -en -ll-yle:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 17.
• the expected product is obtained in the form of a white powder.
• Example 24 12- (dimethylamino) -3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo cyclohexanecarboxylate [11.2.1.0 2 ' 6 .0 0 ] hexadec-13 (16) -en- ll-yle:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• Example 25 12- (dimethylamino) -3,8-dimethyl-4,14-dioxo- 5,9,15-trioxatetracyclo 4-fluorobenzoate [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16) - en-ll-yle:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• Example 26 ll - ⁇ [ter ⁇ -butyl (dimethyl) silyl] oxy ⁇ - 12- (dimethylamino) -3,8-dimethyl-5,9,15-trioxatetracyclo hydrochloride [11.2.1.0 2 ' 6 .0 810 ] hexadec- 13 (16) -ene-4,14-dione:
• Example 27 12- (dimethylamino) -3,8-dimethyl-4,14-dioxo- 5,9,15-trioxatetracyclo heptanoate [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16) -en- ll-yle:
• Example 28 4- (Trifluoromethyl) benzoate of 12- (dimethylamino) -3,8-dimethyl- 4,14-dioxo-5,9,15-trioxatetracyclo [11.2.1.0 2.6 .0 810 ] hexadec-13 ( 16) -en-ll-yle:
• Example 29 12- (dimethylamino) -3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo 2 -thiophenecarboxylate [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16) - en-ll-yle:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• Example 30 3,3- dimethylbutanoate of 12- (dimethylamino) -3,8-dimethyl- 4,14-dioxo-5,9,15-trioxatetracyclo [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16 ) -èn-ll-yle:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• Example 32 12- (dimethylamino) -3,8-dimethyl-4,14-dioxo- 5,9,15-trioxatetracyclo 2 -furoate [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16) - en-ll-yle:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• Example 33 12- (dimethylamino) -3,8-dimethyl-4,14-dioxo- 5,9,15-trioxatetracyclo 5-nitro-2-furoate [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16) -èn-ll-yle:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• Example 34 12- (dimethylamino) - 3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo 2-thiophenecarboxylate hydrochloride [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16 ) -èn- 11-yle:
• Example 35 12- (dimethylamino) -3,8-dimethyl-4,14-dioxo-5,9,15-trioxatetracyclo 2 -thienylacetate [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16) - en-ll-yle:
• Example 36 12- (dimethylamino) -3,8-dimethyl-4,14-dioxo- 5,9,15-trioxatetracyclo phenoxyacetate [11.2.1.0 2 ' 6 .0 810 ] hexadec-13 (16) -en- ll-yle:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• Example 37 4- (8-dimethylamino) -3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro [3,2-c] oxiréno [/] oxacycloundecin-9-yl 4-rt-butylphenylcarbamate:
• Example 38 8- (dimethylamino) -3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro [3,2-c] thien-2-ylcarbamate: 3,2-c] oxireno [/] oxacycloundecin-9-yl:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• Example 40 2 (methylthio) phenylcarbamate 8- (dimethylamino) - 3,10a-dimethyl-2,6-dioxodecahydro-4,7-metheno-furo [3,2-c] oxiréno [/] oxacycloundécin-9-yl :
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 18.
• the expected product is obtained in the form of a white powder.
• Example 41 8- (dimethylamino) -3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro [3,2-c] oxireno [/] oxacycloundecin-9-yl 2-ethoxyphenylcarbamate:
• Example 42 8- (dimethylamino) -3.10a-dimethyl- 2,6-dioxodecahydro-4,7-thien-3-ylcarbamate -4,7-methenofuro [3,2-c] oxireno [/] oxacycloundecin-9-yl:
• Example 43 8- (dimethylamino) -3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro [3,2-c] oxiréno [] oxacycloundecin-9-l-benzothien-3-ylcarbamate:
• Example 44 8- (Dimethylamino) - 3,10a-dimethyl-2,6-dioxodécahydro-4,7-metheno-furo [3,2-c] N- (tc / * - butoxycarbonyl) glycinate [f ⁇ oxacy doundecin-9-yle:
• the organic phase is washed with water and then with saturated sodium chloride solution before being dried over MgSO 4 and filtered.
• the solvent is removed by distillation under reduced pressure.
• the residue is eluted on silica using a mixture of acetone and dichloromethane (40/60).
• the residue is taken up in ether, filtered and dried under vacuum. 25 mg of product are obtained in the form of a white powder.
• Example 45 8- (dimethylamino) -3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro [3,2-c] oxireno-f-oxacycloundecin-9-thien-3-ylacetate:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 44.
• the expected product is obtained in the form of a white powder.
• Example 46 8- (dimethylamino) -3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro [3,2-c] oxireno-[-oxacycloundecin-9-yl-benzothien-3-ylacetate:
• Example 47 8- (dimethylamino) -3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro [3,2-c] thyrophene-3-carboxylate: 3,2-c] oxireno [/] oxacycloundecin-9-yl:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 44.
• the expected product is obtained in the form of a white powder.
• Example 48 8- (dimethylammo) -3,10a-dimethyl- 2,6-dioxodecahydro-4,7-methenofuro [3,2-c] oxiréno [] oxacycloundecin-9-yl 5-phenylthien-2-ylcarbamate:
• Example 49 8- (dimethylamino) -3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro [3,2-c] oxireno-f-oxacycloundecin-9-ye 1-adamantylcarbamate:
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 37.
• the expected product is obtained in the form of a white powder.
• Example 50 8- (dimethylamino) -3,10a-dimethyl-2,6-dioxodecahydro-4,7-methenofuro [3,2-c] oxiréno
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 37.
• the expected product is obtained in the form of a white powder.
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 37.
• the expected product is obtained in the form of a white powder.
• This compound is obtained by a procedure similar to that described for the synthesis of the compound of Example 37.
• the expected product is obtained in the form of a white powder.
• the compounds of Examples 53 to 69 are compounds of general formula (III). These compounds were characterized by their retention time and their peak molecular weight (MH +) as described below.
• the compounds are characterized by their retention time (tr), expressed in minutes, determined by liquid chromatography (CL), and their molecular peak (MH +) determined by mass spectrometry (SM), a simple quadrupole mass spectrometer (Micromass, Platform model) equipped with an electrospray source is used with a resolution of 0.8 da at 50% of valley.
• tr retention time
• MH + molecular peak
• mass spectrometry a simple quadrupole mass spectrometer equipped with an electrospray source is used with a resolution of 0.8 da at 50% of valley.
• Example 56 5 - ⁇ [3- (dimethylamino) -2,2-dimethylpropyl] ammo ⁇ -2-methyl ⁇ 1,3-benzothiazole-4,7-dione:
• Example 65 4- ⁇ 2 - [(2-methyl-4,7-dioxo-4,7-dihydro-1,3-benzothiazol ⁇ 5-yl) amino] ethyl ⁇ benzenesulfonamide:
• the compounds of Examples 70 to 102 are compounds of general formula (IV).
• Example 70 8-bromo-4- [2- (5-methyl-4-imidazolylmethylthio) -ethylamino] - 2-methylthiopyrazolo [1,5-a] -1,3,5-triazine
• Example 71 8-bromo-4- ⁇ 2 - ⁇ [5- (dimethylamino) methyl-2-furannyl] - methyl ⁇ thio ⁇ ethylamino-2-methylthiopyrazolo [1,5-a] -1,3,5-triazine
• This compound was prepared according to the method described in American patent 4,565,815. Mass spectrometry (Electrospray): 459.1.
• Example 72 8-bromo-4- (3- (l-imidazolyl-propylamino) -2-methylthio-pyrazolo [1,5-a] -1,3,5-triazine
• Examples 73 to 80 are prepared according to a procedure analogous to that of Example 72.
• Example 75 8-bromo-2-methylthio-4- (4-pyridylmethylamino) pyrazolo [1,5-a] - 1,3,5-triazine
• Example 78 8-bromo-2-methylthio-4- (4-fluorophenylmethylamino) - pyrazolo [1,5-a] -1,3,5-triazine
• Example 80 8-bromo-2-methylthio-4- [4-N-methylpiperazinyl) anilino] - pyrazoIo [1,5-a] -1,3,5-triazine
• Example 81 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) - 4- (3-chemoroaniino) -pyrazolo [1,5-a] -1,3,5-triazine
• the reaction medium is diluted with chloroform (10 ml) and is washed with an aqueous solution of NaHSO 3 then an aqueous solution of NaHCO 3 .
• the organic phase is dried over MgSO 4 and the solvents are evaporated to dryness under vacuum. 200 mg of a brown solid are obtained.
• Examples 82 to 86 are prepared according to a procedure analogous to that of Example 81.
• Example 82 8-bromo ⁇ 2- (2-aminocyclohexyIamino) -4- (3-chloroaniIino) - pyrazolo [1,5-a] -1,3,5-triazine
• Example 83 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) -4- (3-oxido-pyridylmethyIamino) ⁇ pyrazolo [1,5-a] -1,3,5-triazine
• Example 84 8-bromo-2- (1R-isopropyl-2-hydroxyethylamino) - 4- (3-fluorophenylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine
• Example 85 8-bromo-2- (4'-hydroxyethylpiperazinyl) -4- (3-oxido-pyridylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine
• A1C1 3 are successively added to a solution of 2-methylthio-4- (3-pyridylmethylamino) -pyrazolo- [1,5-a] - 1,3,5-triazine (110 mg) in 15 ml of dichloromethane then 90 ⁇ l of acetyl chloride. The mixture is brought to reflux for 4 hours. After dilution with chloroform (20 ml), the mixture is acidified with dilute HCl, then basified with an aqueous solution of NaHCO 3 and the organic phase recovered is dried over MgSO 4 . The solvents are removed by dry evaporation under vacuum.
• Example 90 8-dimethylaminomethyl-4- (3-pyridylmethylamino) - 2-methylthiopyrazolo [1,5-a] -1,3,5-triazine
• Example 93 8 - [(1,3-dihydro-2-oxoindol) -3-ylidenemethyl) -2-methylthio- 4- (3-pyridylmethylamino) pyrazolo [1,5-a] -1,3,5-triazine
• This compound is prepared according to a procedure analogous to that described for intermediate 81.1. Dark yellow powder. Melting point: 70-71 ° C
• Example 96 8-bromo-2-methylthioxo-4- (3-chloroanilino) pyrazolo [1,5-a] -1,3,5-triazine
• This compound is prepared by heating at reflux a mixture containing the compound of Example 91 (1 equivalent), hydroxylamine hydrochloride (2 equivalents), sodium formate (10 equivalents) and formic acid (100 equivalents) (cf. J. Chem. Soc. (1965), 1564). Solid pale yellow. Mass spectrometry (Electrospray): 298.2.
• Example 100 2-methylthio-4- (3-pyridylmethylamino) pyrazolo [1,5-a] - 1,3,5-triazine
• Cupric nitrate (70 mg) is added to a suspension of 2-methylthio- 4- (3-pyridylmethylamino) -pyrazolo [1,5-a] -1,3,5-triazine (50 mg; compound of the example 100) in 6 ml of acetic anhydride.
• the mixture is stirred at room temperature overnight before being partitioned between chloroform and a saturated aqueous solution of NaHCO 3 .
• the organic phase is dried over MgSO 4 and the solvents are evaporated to dryness under vacuum.
• the residue is subjected to preparative chromatography on silica gel using a chloroform-methanol mixture (15: 1) as eluent. The appropriate fraction is isolated and extracted with the chloroform methanol mixture.
• the HT-29 cell line (human colon cancer cells) was acquired from the American Tissue Culture Collection (Rockville, Maryland, USA).
• these cells are seeded in 90 ⁇ l of Eagle medium modified by Dulbecco (Gibco-Brl, Cergy-Pontoise, France) supplemented with 10% fetal calf serum inactivated by heating (Gibco-Brl, Cergy-Pontoise, France), 50,000 units / 1 of penicillin and 50 mg / 1 of streptomycin (Gibco-Brl, Cergy-Pontoise, France), and 2 mM of glutamine (Gibco-Brl, Cergy-Pontoise, France).
• the cells were treated simultaneously with concentrations of the test compounds alone or in combination for 120 hours.

Landscapes

• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Inorganic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=8863791

Family Applications (1)

Country Status (13)

Families Citing this family (16)

Family Cites Families (4)

• 2001
  • 2001-05-30 FR FR0107104A patent/FR2825278A1/fr not_active Withdrawn
• 2002
  • 2002-05-29 HU HU0400153A patent/HUP0400153A2/hu unknown
  • 2002-05-29 EP EP02738284A patent/EP1438039A2/fr not_active Withdrawn
  • 2002-05-29 WO PCT/FR2002/001800 patent/WO2002096348A2/fr not_active Application Discontinuation
  • 2002-05-29 US US10/478,387 patent/US20040138245A1/en not_active Abandoned
  • 2002-05-29 CN CNA028125924A patent/CN1691941A/zh active Pending
  • 2002-05-29 JP JP2002592861A patent/JP2004533456A/ja not_active Abandoned
  • 2002-05-29 KR KR10-2003-7015600A patent/KR20040025922A/ko not_active Application Discontinuation
  • 2002-05-29 CA CA002448528A patent/CA2448528A1/fr not_active Abandoned
  • 2002-05-29 PL PL02369148A patent/PL369148A1/xx not_active Application Discontinuation
  • 2002-05-29 RU RU2003137833/15A patent/RU2003137833A/ru not_active Application Discontinuation
  • 2002-05-29 CZ CZ20033549A patent/CZ20033549A3/cs unknown
  • 2002-05-30 AR ARP020102025A patent/AR034059A1/es not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events